EBV transformation in conjunction with limiting dilution culture and somatic hybridization techniques have been used to establish cell lines capable of making human mAbs to a number of self-antigens, e.g., ssDNA, thyroglobulin, insulin, IgG, Fc fragment and exogenous antigens, e.g., tetanus toxoid. These technologies have been ap- plied to the study of the human B cell repertoire in patients with SLE, rheumatoid arthritis, Hashimoto's disease and insulin-dependent diabetes mellitus. B lymphocytes producing two groups of autoantibodies were detected in these patients. The first one includes mAbs binding to multiple self and exogenous antigens, in general, with low affinity. These polyreactive antibodies can also be detected in healthy subjects and are produced by CD5+ B cells. The second one includes high affinity monoreactive autoantibodies and is found only in autoimmune patients. In other experiments, we generated human mAbs to rabies virus in subjects previously vaccinated with the appropriate virus-inactivated vaccine, as well as monoreactive rheumatoid factor mAbs from a single patient with rheumatoid arthritis. Five of these mAbs displayed a high binding affinity for rabies virus components and one neutralized the virus. The gene segments coding for the V region of polyreactive antibodies have been sequenced and found to be in germline configuration. In contrast, the gene encoding the valuable regions of the monoreactive monoclonal RF autoantibodies, as well as the high affinity mAbs to rabies virus displayed a number of somatic mutations consistent with a process of antigen-driven clonal selection.